Disability threatens the independence of many older adults and results in substantial late-life health care needs and associated expenditures. Sarcopenia plays a central role in disability. Our long-term goals are to gain insight into the processes that underlie the development of sarcopenia and disability and to identify possible strategies for preventive or therapeutic interventions. In the first three cycles of this R01, we examined the relationships of oxidative stress, advanced glycation end products, and klotho with loss of muscle strength, decline in physical performance, disability, and mortality in older adults. In the fourth cycle, we will validate the relationship between circulating metabolites and the age-related decline in muscle quality. Our recent studies demonstrate that muscle quality, defined as the amount of strength generated by a unit of muscle mass, has a linear decline with older age. The biological pathways that lead to the age-related decline in muscle quality are not well understood. Animal studies show that there are circulating factors, most of which are uncharacterized, that rejuvenate aging skeletal muscle. Using a targeted metabolomics approach, our preliminary studies suggest that circulating polyamines, methionine, and tryptophan are related to muscle quality in older adults. We hypothesize that low putrescine, high methionine, and high tryptophan in the circulation are independent predictors of decline in muscle quality, and that the trajectories of plasma putrescine, methionine, and tryptophan are strongly associated with trajectories of muscle quality over time. The specific aims are to characterize the relationship between circulating (1) polyamines, (2) methionine, and (3) tryptophan with the age-related decline of muscle quality in adults. To address these hypotheses, we will measure circulating metabolites in 523 adults in the Baltimore Longitudinal Study of Aging who were followed longitudinally with serial measurements of muscle quality between January 2006 and December 2014. Plasma metabolites will be measured at each visit over time using liquid chromatography-tandem mass spectrometry. These metabolites are potentially modifiable risk factors, and validation of their relationships with the age-related decline in muscle quality may drive new investigations that target their metabolic pathways.